This patent application describes various routes used to prepare the fungicidal macrocyclic picolinamides. It may be advantageous to provide more direct and efficient methods for the preparation of the fungicidal macrocyclic picolinamides and related compounds, e.g., by the use of reagents and/or chemical intermediates that provide improved time and cost efficiency.
Provided herein are processes for the alkylation of picolinamides, including compounds of Formula (I):

with a substituted chloroacylal of Formula (II):

to produce a structure of Formula (III):

wherein: R1 is a primary or secondary alkyl group;                R2 is a heterocycle containing 5-12 atoms including 1-3 heteroatoms selected from the group consisting of N, O, P, and S with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 acyl, ═O, benzyl, C1-C6 alkyl ether, or aryl ether; and        R3 is a primary, secondary, or tertiary alkyl group.        
In some exemplary embodiments, the picolinamide of Formula (I) is alkylated with the chloroacylal of Formula (II) in an organic solvent utilizing a crown ether phase-transfer catalyst, an inorganic iodide co-catalyst, and a metallic carbonate.
In one exemplary embodiment, the picolinamide is UK-2A (CAS No. 167173-85-5), (3S,6S,7R,8R)-8-benzyl-3-{[(3-hydroxy-4-methoxypyridin-2-yl)carbonyl]amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate], of the Formula (IV):

In one exemplary embodiment, UK-2A is alkylated with chloromethyl isobutyrate (CAS No. 61644-18-6) of Formula (V):
to form the structure of Formula (VI). Formula (VI) is (3S,6S,7R,8R)-8-benzyl-3-{[(4-methoxy-3-{[(2-methylpropanoyl)oxy]methoxy}-pyridin-2-yl)carbonyl]amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate]. Other by-products, such as the compound of Formula (VII), may also be formed. One advantage of the process disclosed herein is that it disfavors the formation of the compound of Formula (VII), thereby increasing the yield of the more desirable product of Formula (VI).

Throughout the disclosure, references to the compounds of the present disclosure are read as also including optical isomers and salts. Specifically, when compounds of the present disclosure contain a stereogenic carbon, it is understood that such compounds may include optical isomers, diastereomers and racemic and non-racemic mixtures thereof. Exemplary salts may include: Hydrochloride, hydrobromide, hydroiodide, and the like. Compounds containing carbon-carbon double bonds may be present as E, Z or E/Z mixtures.
Certain compounds disclosed in this document can exist as one or more isomer. It will be appreciated by those skilled in the art that one isomer may be more biologically active than the others. The structures described in the present disclosure are generally drawn in one geometric form representing the major stereoisomer present, and are not intended to represent all possible geometric and tautomeric forms of the molecule that may be present. In situations where the configuration of a particular stereogenic carbon atom is not known or is a mixture of similar amounts of each stereoisomer, the structure may be drawn without indication of the absolute configuration (i.e., no solid or dashed, wedge bond may be used).
The embodiments described above are intended merely to be exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific processes, materials and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.